1. Field of the Invention
This invention relates to recombinant DNA molecules and in particular to recombinant vectors for use in the transformation of a microbial host which contain inserted fragments carrying one or more genes involved in the regulation of clavulanic acid biosynthesis and cephamycin biosynthesis.
Progress in understanding the process of regulation of secondary metabolites produced by micro-organisms such as Streptomyces clavuligerus has been slow although it has been established that common control mechanisms may be responsible for the switching on of secondary metabolism in S. coelicolor. Two of the secondary metabolites produced in S. clavuligerus, clavulanic acid and cephamycin C, are important as antibiotics but appear to have totally unrelated pathways and nothing is currently known of how these pathways are regulated. In particular clavulanic acid is of great clinical value since it is a beta-lactamase inhibitor and protects beta-lactamase-labile beta-lactam antibiotics from degradation. Methods for increasing the yield (titre) of clavulanic acid in fermentation processes are therefore of considerable commercial importance.
2. Description of the Related Art
One approach to the problem of clavulanic acid yield improvement involves the use of recombinant DNA technology using S. clavuligerus as the host cell. Several enzymes are believed to be involved in clavulanic acid biosynthesis and the gene or genes encoding a clavaminic acid synthase, which converts one clavulanic acid intermediate, proclavaminic acid, into another one, clavaminic acid, have been cloned (European Patent Application, Publication Number 0 349 121). However, no genes concerned with the regulation of enzymes have so far been identified.